Action Points

Edoxaban, a novel factor Xa inhibitor, met its primary endpoints in a trial that pitted it against warfarin for treatment of symptomatic venous thromboembolism, a study found.

Note that edoxaban appeared to work best in the highest-risk patients and was associated with significantly less bleeding compared with warfarin.

AMSTERDAM -- Edoxaban, a novel factor Xa inhibitor, met its primary endpoints in a trial that pitted it against warfarin for treatment of symptomatic venous thromboembolism (VTE).

Among more than 8,000 patients with deep-vein thrombosis (DVT) or pulmonary embolism (PE), 130 (3.2%) of the patients treated with edoxaban had a recurrent, symptomatic VTE versus 146 (3.5%) warfarin-treated patients, a hazard ratio of 0.89 (95% CI 0.70-1.13, P<0.004 for non-inferiority), Harry R. Büller, MD, of the Academic Medical Center, Amsterdam, reported in a Hot Line session at the European Society of Cardiology meeting here.

The safety endpoint was bleeding (major or clinically relevant non-major bleeding), and in that analysis edoxaban was superior to warfarin, as 8.5% of the edoxaban patients had bleeding events versus 10.3% of the patients in the warfarin group (P=0.004 for superiority).

Moreover, edoxaban appeared to work best in the highest-risk patients -- 938 patients with pulmonary embolism and right ventricular dysfunction assessed by N-terminal pro-brain natriuretic peptide levels. In those patients, the recurrent VTE rate was 3.3% in the edoxaban group versus 6.2% in the warfarin group, Büller said.

Based on the results in that very high risk population, Büller predicted that clinicians treating those patients will consider that efficacy profile when selecting an oral Factor Xa inhibitor.

In the highly competitive oral anticoagulant group, those numbers look good, but at first blush the two already approved Factor Xa inhibitors, rivaroxaban (Xarelto) and apixaban (Eliquis) looked better when they were studied in VTE.

In EINSTEIN-VTE, rivaroxaban had a recurrent symptomatic VTE rate of 2.1%, and 8.1% of patients met the safety endpoint.

Likewise, in another VTE trial -- AMPLIFY-EXT -- apixaban (2.5 mg or 5 mg twice a day) had a recurrent or VTE-related death rate of 1.7%, and 3.2% of the patients who received low-dose apixaban reached the safety endpoint, as did 4.3% of patients treated with 5 mg of apixaban.

Patrick T. O'Gara, MD, American College of Cardiology president-elect, praised the design of the trial, but he agreed that "for mortality benefit, apixaban does appear to have the edge."

That apixaban benefit, O'Gara said, is militated by the fact that patients need to take the drug twice daily, while "edoxaban is once a day, as is rivaroxaban."

Asked if there was a specific population that might benefit from edoxaban versus rivaroxaban or apixaban, O'Gara, who is director of clinical cardiology at Brigham and Women's Hospital and a professor at Harvard Medical School, said the findings from the Hokusai researchers did not provide that answer.

The attempt at a cross-trial comparison drew harsh criticism from Elliott Antman, MD, principal investigator in a trial of edoxaban for prevention of stroke in patients with atrial fibrillation (ENGAGE-AF).

Antman, who like O'Gara is a Harvard professor, said that comparing the edoxaban VTE results to EINSTEIN-VTE or AMPLIFY-EXT would only lead to false conclusions. "You could repeat the rivaroxaban trial 100 times and still not achieve data that can be compared."

Stavros V. Konstantinides MD, PhD, of the Medical University in Mainz, Germany, who was the ESC discussant for the paper, said that, despite the advantage of once-daily dosing of edoxaban, “apixaban has the best safety profile so far.”

Moreover, unlike the VTE studies of apixaban and rivaroxaban, all patients in the Hokusai trial received heparin for 5 days. After that heparin run-in, patients were randomized to edoxaban or to warfarin. The median duration of heparin after randomization was 7 days.

Antman said that design best replicated real-world clinical practice, in which heparin is usually started before warfarin.

Buller noted that he was an investigator for the EINSTEIN-VTE study, "and after that the thinking was maybe we don’t need low molecular weight heparin, but now I think we need to reconsider that assumption."

The Hokusai-VTE trial recruited 4,921 patients with DVT and 3,319 patients with PE. Patients initially were treated with heparin, and then were randomized to edoxaban (60 mg or 30 mg) or warfarin. There was an overlap of the heparin therapy when warfarin was started.

During a press conference, Keith Fox, MBChB, chair of the ESC scientific program, asked Buller if that overlap could have increased bleeding risk in the warfarin arm, thus introducing bias, but Buller said the overlap merely allowed warfarin to reach therapeutic range.

The edoxaban regimen “may be less handy, especially for early-discharge patients… [though] some doctors may feel more comfortable starting with low molecular weight heparin and then switching to edoxaban for the one-third of patients with severe PE,” Konstantinides said.

He added, “The NOACs [new oral anticoagulants] have shown efficacy and safety. Now, the test under real life conditions begins. They have to prove efficacy and safety there. I expect that. And they now must justify the high cost by showing … an improvement in patient treatment satisfaction and quality of life and, hopefully, a reduction in healthcare costs … with lower hospitalizations.”

The average age of patients in the Hokusai study was 56-57, and just over half were men.

Patients were enrolled from January 2011 through October 2012 at 439 centers in 37 countries.

About 40% of patients were treated for a year, and 80% of the edoxaban group was adherent to study treatment. Among the warfarin patients, average time in therapeutic range was 63.5%.

The study was supported by Daiichi-Sankyo, which is developing edoxaban.

Buller reported personal fees from Daichi Sankyo during the study, as well as grant support and personal fees from Bayer Health Care and Pfizer. He also received personnal fees from Boehringer Ingelheim, Bristol-Myers Squibb, Isis Pharmaceuticals, and ThromboGenics outside the submitted work.

Antman has a research grant from Daiichi-Sankyo through Brigham and Women's Hospital. O'Gara said he had no financial disclosures.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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